16-cyano and 16-cyanoalkyl 3, 20-dioxy-genated pregnenes



16-CYANO AND IG-CYANOAIJKYL 3,20-DIOXY- GENATED PREGNENES Robert H. Mazur, Evauston, 111., assignor to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware No Drawing. Application March 20, 1956 SerialNo. 572,629

5 clarinet-:1 1

Thisinventiod'relates to 1"6- cya'no and ieey nenr r derivatives of 3,20-dioxyg'enatefl *preg'nenes, and processes" for the manufacturethe'reof. More particularlyfthisf invention relates to p'regnenesof the; formula the characteristic double bond is ordinarily disposed between carbons 5 and 6. On the other hand, when X represents carbonyl v the double bond is commonly conjugated-i. e., in the 4position.

As to the cyanoalkyl radicals comprehended by Y in the generic formula, these are preferably lower alkyl radicals-such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, secondary normal pentyl, primary isopentyl, secondary isopentyl, tertiary pentyl, and sundry hexyl, heptyl, and octyl radicals-substituted in each instance by a single cyano radical.

The compounds of this invention possess valuable pharmacological properties Especially, the subject compounds are useful because of their selectiveanti-cortisone activity. Administered conjointly withcortisoneytheyblock the 'atrophying influence thereofon lymph nodes and thymus, and appear to inhibitin particular-spe-I' rites Patent lone- -for example, I '3-hydroxypregna-5,l6-dien -one-- which is esterified, to protect--the hydroxyl group, then;

converted to a 16-cyano derivative by interaction at elevated temperatures in a solvent mediumwith hydrogen cyanideor a salt thereof-tor example, potassium cyanide.

Where saponification-is notlachieved. in process, this is effected bysubse'quent treatment. with alkali; The.16-.

, 3-acetoxypregna 5;16-dien 20-one+said adduct being derived in absolute alcohol solution, using metallic sodium or sodium ethoxide as a condensing agent. Saponification of the ester adduct, followed by a short heating period at around 300 centigrade to bring about decarboxylation, affords the desired l6-cyan0methyl-3- hydroxy compound. This materialanother of the hereinafter claimed compoundsis, like the homologous 16- cyano material aforesaid, converted to the corresponding aeoxo compoundof the, claims by Oppenauer oxidation; 1

The'following. examples describe in detail certain of the.compoundsillustrative of thepresent invention, and: methods which-have been devised for their. manufacture:

However,-theinvention is :not to be construed ."as limited therebyneither int spiriti or in. scope, since .it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods may be practiced without departing from the purpose and intentof'this disclosure. In the examples herein.- after detailed, temperatures are given in degrees centigrade C.) and relative amounts of materials in parts by weight, except as otherwise noted Specific rotations refer to'the D lineof sodium and were determined iu methyl alcohol solution at room temperature Example 1 1riot-cyano-3t3-hydroxypregn-5-en-20-one.-A suspension of 20 parts of 3fi-acetoxypregna-5,16-dien-20-one and 20 parts of potassiunrcyanide in a mixture of 315 parts of methyl alcohol, 36 parts of ethyl acetate, and

Example "2" 16a-cyanopi'egri-4-ene-3i20-di0ne.-A solution of 22" Patented Deer 24, -7.

mixture 'of 870 "partsbf toluene and 209 parts of cyclohexanone isazeotropically dried by brief distillation. A

i CH:

. Example 3 Ethyl 3 8 hydroxy 20 oxopregn 5 en-l6a-cyanoacetate.-To a solution of 14 parts of sodium and 68 parts of ethyl cyano-acetate in 800 parts of absolute alcohol is added 107 parts of 3,8-acetoxypregna-5J6-dien-20- one. The mixture is agitated at room temperature until the steroid is dissolvedabout one and one-half hours ordinarily being requiredand the resultant solution then let stand at room temperatures overnight sans further agitation. The solution is next neutralized with acetic acid, following which it is concentrated under reduced pressure. Excess ethyl cyanoacetate is finally pumped all under high vacuum. The residue is chromatographed on silica gel. Elution With 20% ethyl acetate in benzene affords the desired ethyl 3fl-hydroxy-20-oxopregn-5-enl6a-cyanoacetate which, crystallized from ethyl acetate, is obtained as short needles, M. P. 196198 C. The product has the formula -CHC O OCrHs Example 4 16u-cyan0methyZ-SB-hydroxypregn-S-err-20-0ne.-A solution of 64 parts of the ethyl cyanoacetate adduct obtainable by the procedure of the foregoing Example 3 in 650 parts of dioxane, is diluted with 195 parts of water containing, in solution, approximately parts of caustic potash. The reactants are heated under gentle reflux for one-half hour, then neutralized with acetic acid and diluted with 200 parts of water. Concentration under reduced pressure results in precipitation of the deesterified adduct, which is isolated by extraction into chloroform. The chloroform extract is stripped of solvent and the residue thereupon decarboxylated by heating at 280 300 C. for three-quarters of an hour. Crystallization of the product thus obtained from ethyl acetate afiords 16a-cyanomethyl-3/i-hydroxypregn-5-en-20-one as tiny needles, M. P. 206207 C. The product has the formula Example 5 16a cyanomethylpregn-4-ene-3,20-a'ione.A solution of 52 parts of 16q -cyanomethyl-3 3-hydroxypregn-5-en-20- one in 1740 parts of toluene is azeotropically dried by brief distillation. There is then added 235 parts of cyclohexanone and a solution of 53 parts of aluminum isopropoxide in 220 parts of dry toluene. The resultant mixture is heated at reflux temperatures, with agitation, for 2 hours. Approximately 3000 parts of 50% aqueous Rochelle salt solution is next introduced, whereupon cyclohexanone is removed by steam distillation. The desired 16a-cyanomethylpregn-4-ene-3,20-dione is isolated from the distilland by extraction with ether. Evaporation of solvent and chromatographic purification of the residue on silica gel, using benzene and ethyl acetate as developing solvents, affords the purified product, whichcrystallized from a mixture of benzene and cyclohexaneis obtained as rectangular prisms, M. P. -186 C. The product has the formula What claimed is: 1. A compound of the formula IGY References Cited in the file of this patent [U ITED STATES PATENTS 2,697,109 Dodson Dec. 14, 1954 2,708,201 Qodson et a1. May 10, 1955 UNITED STATES PATENT OFFICE Certificate of Correction Patent N 0. 2,817,671 December 24, 1957 Robert H. Mazur It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, Exam e 5, the formula should appear as shown below instead as in the patentf *OHaON same column 4, line 67, claim 3, for 16a-cyan0pregn-4-ene-3,-20-di0ne read -16a-cyanopregn--ene-3,20-dione-.

Signed and sealed this 25th day of March 1958.

[sEAL] Attest KARL H. AXLINE, Attestng Oficer.

ROBERT C. WATSON, Oommz'ssz'oner of Patents. 

1. A COMPOUND OF THE FORMULA 